1. Field of the Invention
The present invention relates to a regioselective method for making 3-amino-2-chloro-4-methylpyridine from acetone and ethyl cyanoacetate.
2. Description of Related Art Including Information Disclosed Under 37 CFR 1.97 and 1.98
As described in U.S. Pat. No. 5,366,972, the compound 3-amino-2-chloro-4-methylpyridine is useful as an intermediate material for the synthesis of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazep in-6-one, an HIV reverse transcriptase inhibitor useful for the treatment of HIV-1, known as nevirapine.
There are several known methods for the synthesis of 3-amino-2-chloro-4-methylpyridine. An early synthesis, beginning from 2-chloro-4-methyl-3-nitropyridine, has been described by Chapman et al. (J. Chem. Soc. Perkin Trans. I, 2398-2404 (1980)). As reported by Grozinger et al. (J. Heterocyclic Chem., 32, 259 (1995)), the compound has been synthesized in small laboratory batches by nitrating the readily available 2-amino-4-picoline or 2-hydroxy-4-picoline. This procedure suffers from non-selective nitration at positions 3 and 5, as well as thermo-chemical hazards and potential for "run-away" when carried out in large. The drawbacks of the nitration-based process lead to the development of two related synthetic routes starting from ethylacetoacetone and cyanacetamide, as described in U.S. Pat. Nos. 5,668,287 and 5,200,522. Both of the latter two synthetic routes require the dichlorination of the intermediate 2,6-dihydroxy-4-methyl-3-pyridinecarbonitrile, at positions 2 and 6, subsequent de-chlorination and finally selective re-chlorination at position 2. The di-chlorination and dehalogenation, as well as the selective monochlorination at position 2 require special manufacturing equipment that is expensive and which may not be readily available. Yet another synthesis, comprising the steps chlorination of ethyl cyanoacetate, Michael addition with crotonaldehyde, cyclization, conversion to the amide and finally reduction to the amine has been described by Zhang et al. (Tetrahedron 51(48), 13177-13184 (1995)), who report that while the desired product was obtained, the Michael addition was slow and the cyclization low-yielding. Schneider (U.S. Pat. No. 5,686,618) has provided a synthesis involving the reduction of 2,6-dichloro-3-amino-4-methylpyridine and monochlorination using H.sub.2 O.sub.2 in HCI without isolation of the intermediate 3-amino-4-picoline. A synthesis beginning with 2-chloro-3-aminopyridine has been disclosed by Nummy (U.S. Pat. No. 5,654,429).